Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection

Abstract

Progesterone is being utilized as a therapeutic means to ameliorate neuron loss and cognitive dysfunction following traumatic brain injury. Although there have been numerous attempts to determine the means by which progesterone exerts neuroprotective effects, studies describing the underlying molecular mechanisms are lacking. What has become clear, however, is the notion that progesterone can thwart several physiological processes that are detrimental to neuron function and survival, including inflammation, edema, demyelination and excitotoxicity. One clue regarding the means by which progesterone has restorative value comes from the notion that these aforementioned biological processes all share the common theme of eliciting pronounced increases in intracellular calcium. Thus, we propose the hypothesis that progesterone regulation of calcium signaling underlies its ability to mitigate these cellular insults, ultimately leading to neuroprotection. Further, we describe recent findings that indicate neuroprotection is achieved via progesterone block of voltage-gated calcium channels, although additional outcomes may arise from blockade of various other ion channels and neurotransmitter receptors. This article is part of a Special Issue entitled 'Neurosteroids'.

Figure 1. Putative mechanism for progesterone mediated neuroprotection

A) Excitotoxic insult is characterized by the influx of both sodium and calcium-ions through glutamate receptors leading to depolarization-induced opening of L-type calcium channels. Calcium flux through L-type calcium channels contributes to calcium overload and subsequent activation of various calcium-mediated death pathways. B) Through an unknown mechanism, extracellular application of progesterone (P) inhibits the influx of calcium ions through L-type calcium channels, protecting the neuron from excitotoxic death.